The goal of this Program Project is to understand how injury, regeneration, and alterations in neural activity affect synaptic and network function and to explore the mechanisms that either promote or impede recovery. We are motivated in particular by knowledge that voluntary movement remains impaired following peripheral nerve injury, even after successful nerve regeneration. Five projects, each led by an NIH funded investigator who brings unique experimental expertise and conceptual insight to the program, will advance our fundamental understanding of the changes that occur in synapses and cells in spinal locomotor circuits following peripheral nerve injury with or without reinnervation of muscle. Project 1 will apply electrophysiological methods in vivo to examine cellular and network mechanisms in the spinal cord suspected of preventing recovery of sensorimotor function following nerve regeneration. Project 2 will examine the extent to which reformation of inhibitory synapses on injured/regenerating neurons alters their properties. The structure, molecular and neurochemical organization of inhibitory synapses on motoneurons axotomized after peripheral nerve injuries will be analyzed with confocal and electron microscopy. Possible alterations will be analyzed in the context of parallel injury-evoked plasticity at excitatory synapses and the progression of peripheral regeneration and muscle reinnervation. The resultant functional properties will be investigated with in vivo electrophysiology using the recurrent and reciprocal inhibitory circuits as test synapses. Project 3 will establish the rules that govern changes in synaptic strength that result from chronic mismatches of pre- and postsynaptic activity following injury to the nervous system. This aim will use voltage-clamp techniques applied to the activity-manipulated neuromuscular injunction. Project 4 will study molecular mechanisms of transmitter release to better understanding of how injury can lead to an increase in synaptic strength via increased size of the presynaptic quantum. A simple model synapse (neuromuscular junction) and a simple model of neuronal circuits (hippocampal neurons in culture) in normal and RabSA mutant mice will be examined using patch-clamp recording. Project 5 will elucidate mechanisms by which peripheral nerve injury alters the sub-cellular distribution and clustering of membrane ion channels on motoneurons, and will examine the functional effects of altered channel localization and properties on intrinsic neuronal excitability and integration. This aim will combine computational modeling with confocal imaging and electrophysiology in vivo. The five projects interact and add significant value to each other to attack these complex problems, and they are coordinated together with a shared Imaging Core to progress in ways that cannot be accomplished by a collection of independent research projects. The Program Project will yield new information about synaptic and circuit adaptations and in this way accelerate discovery of effective means of promoting recovery from neurotrauma.